Ibuprofen Affects the Tissue Distribution of Sunitinib to Liver Differently in Male and Female Mice

I Segarra1,2, ST Chan1, HW Khoo1, CLL Lau1, M Selvaratanam1. 1International Medical University, Department of Pharmaceutical Technology, 57000-Kuala Lumpur, Malaysia, 2Universitat Internacional de Catalunya, Faculty of Medicine and Health Sciences, 08195-Sant Cugat (Barcelona), Spain

Background: Sunitinib is an anticancer agent approved to treat advanced renal cell carcinoma and gastrointestinal stromal tumors refractory to imatinib. It is a multi-targeted receptor tyrosine kinase inhibitor which inhibits cellular signaling by targeting PDGF-R, VEGF-R, c-KIT, RET, CSF-1R and flt3. Anticancer drugs present diverse drug-drug interactions with pain-management NSAIDs including ibuprofen which is evaluated upon coadministration with sunitinib. Methods: Ibuprofen 30 mg/kg (study group) or vehicle (control group) was administered orally to male and female Balb/c mice (n = 5 per group, 10-12 week old, 20-25 g) and 30 min later a 60 mg/kg dose of sunitinib was administered orally. At pre-scheduled time points (5, 15, 30 min, 1, 2, 4, 6, 12, 16 h) mice were euthanized, blood sample collected and the liver harvested and kept at -30°C. After samples were processed, sunitinib concentration in plasma and liver were measured using a validated HPLC method. Pharmacokinetic parameters were estimated using non-compartmental analysis. Results: Sunitinib plasma AUC0 → ∞ was higher in female (95.6 µg·h/mL) than male (52.84 µg·h/mL) mice, p<0.05 (based on Bailer’s method for sparse or destructive sampling). Plasma CMAX was also higher in female mice, 21.45 ± 21.42 versus 5.58 ± 2.32 µg/mL in male mice but was not significant. In liver, sunitinib exposure was 1516 µg·h/mL for female and 1807 µg·h/mL for male mice (p<0.05) and CMAX was higher in female, 251 ± 95 µg/mL versus 214 ± 110 µg/mL in male but was not significant (p>0.05). Sunitinib plasma AUC0 → ∞ after ibuprofen coadministration increased 12% in male mice and decreased 62% in female mice and was statistically significant (p<0.05). Plasma CMAX decreased 43% in male mice and 63% in female mice (p>0.05). In liver, the AUC0 → ∞ increased 26% in male mice and decreased 13% in female mice (p<0.05). However, liver CMAX decreased 8% and 15% in male and female mice respectively but no differences were found between male and female mice. Conclusions: There were gender based AUC0 → ∞ significant differences in plasma and liver. After ibuprofen coadministration, plasma sunitinib exposure decreased in male and female mice but had opposite effect in liver AUC0 → ∞: lower for female mice and higher for male mice. These differences in plasma and tissue exposure together with ibuprofen drug-drug differential interaction effect may explain sex based differences in sunitinib toxicity. Furthermore, coadministration of ibuprofen may lead to a drug-drug interaction which is not put forward only after plasma pharmacokinetic analysis masking toxicity. Thus, sunitinib and ibuprofen coadministration may render monitoring of hepatic function.